As chemical engineers seek to improve plant safety, reliability, and financial performance, a wide range of uncertaintyladen decisions need to be made. It is widely agreed that probabilistic approaches provide a rational framework to quantify such uncertainties and can result in improved decision making and performance when compared with deterministic approaches. This article proposes a novel method for design and performance analysis of chemical engineering processes under uncertainty. The framework combines process simulation tools, response surface techniques, and numerical integration schemes applied in structural reliability problems to determine the probability of a process achieving a performance function of interest. The approach can be used to model processes in the presence or absence of performance function(s), with or without parameter interactions, at both design and operational phases. With this, process behavior can be quantified in terms of stochastic performance measures such as reliability indices and the associated most probable process design/operating conditions, providing a simple way to analyze a wide range of decisions. To validate the applicability of the proposed framework, three case study systems are considered: a plug flow reactor, a heat exchanger, and finally a pump system. In each case, performance criteria based on the original physical model and the surrogate model are set up. Reliability analysis is then carried out based on these two models and the results are assessed. The results show that the proposed framework can be successfully applied in chemical engineering analysis with additional benefits over the traditional deterministic methods.